Regorafenib was reviewed under the FDA’s priority review program, which provides an expedited six-month review for drugs that may provide safe and effective therapy when no satisfactory alternative therapy exists, or for drugs that offer substantial improvement compared with marketed products. The drug was also granted orphan product designation because it is intended to treat a rare disease. According to the National Cancer Institute, an estimated 3,300 to 6,000 new cases of GIST occur yearly in the United States, mostly in older adults.

The approval was based on the results of an international randomized, double-blind, placebo-controlled trial of 199 patients with histologically confirmed metastatic or unresectable GIST who experienced disease progression while on, or intolerance to, previous imatinib and disease progression while on previous sunitinib. Patients were randomly assigned (2:1) to receive either oral regorafenib 160 mg daily (n=133) or placebo (n=66) for the first 3 weeks of each 4-week cycle. All patients also received best supportive care, which included treatments to help manage side effects and symptoms of cancer.

Patients in the study took regorafenib or placebo until their cancer progressed or the side effects became unacceptable. Patients who received placebo were given the opportunity to switch to regorafenib when their cancer progressed. The primary endpoint was progression-free survival (PFS). Median PFS was 4.8 months (IQR 1.4–9.2 months) for patients who received regorafenib and 0.9 months (IQR 0.9–1.8 months) for patients who received placebo (hazard ratio of progression 0.27, 95 percent confidence interval: 0.19, 0.39; p<0.0001). After disease progression, 56 patients assigned to receive placebo (85 percent) crossed over to receive regorafenib treatment.

Serious side effects, which occurred in less than one percent of patients, were liver damage, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks and perforations (holes) in the intestines.

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Previously Treated Metastatic Colorectal Cancer

On September 27, 2012, the Food and Drug Administration (FDA) approved regorafenib (Stivarga® tablets, made by Bayer HealthCare Pharmaceuticals, Inc.) for the treatment of patients with metastaticcolorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, with an anti-VEGF therapy, and, if KRAS wild type, with an anti-EGFR therapy.

The approval was based on the results of an international randomized (2:1), double-blind, placebo-controlled trial (Study 14387) that enrolled 760 patients with previously treated mCRC. All patients had received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and with the anti-VEGF therapy bevacizumab. All but one of the patients with KRAS wild-type tumors received the anti-EGFR therapies panitumumab or cetuximab. Patients in the regorafenib arm received 160 mg regorafenib orally once daily for the first 21 days of each 28-day cycle, plus best supportive care. Those in the control group received matching placebo with best supportive care.

The trial also demonstrated a statistically significant improvement in progression-free survival in patients who received regorafenib [HR 0.49 (95 percent CI: 0.42, 0.58); p<0.0001]. Median progression-free survival was 2.0 months (95 percent CI: 1.9, 2.3) in the regorafenib group and 1.7 months (95 percent CI: 1.7, 1.8) in the placebo group. No difference in overall response rate was observed. Five patients (1 percent) in the regorafenib group and one patient (0.4 percent) in the placebo group experienced partial responses.

The safety population in Study 14387 comprised 500 patients who received regorafenib and 253 patients who received placebo. The most frequently observed adverse drug reactions (in at least 30 percent of patients) in those receiving regorafenib were asthenia/fatigue, decreased appetite and food intake, hand-foot skin reaction, diarrhea, mucositis, weight loss, infection, hypertension and dysphonia.

The most serious adverse drug reactions in patients receiving regorafenib were hepatotoxicity, hemorrhage, and gastrointestinal perforation. Regorafenib is approved with a boxed warning describing the risk of hepatotoxicity.

The recommended dose and schedule for regorafenib is 160 mg (four 40 mg tablets) orally once daily for the first 21 days of each 28-day cycle.